1. Field of the Invention
Cardiac arrhythmias are disorders of impulse generation that result from disruptions of normal cardiac pacemaker activity, from disturbances in cardiac conductive fibers, or from a combination of both. Cardiac arrhythmias of clinical significance in man include: premature contractions (extrasystoles) originating in atrial or ventricular foci; paroxysmal supraventricular tachycardia; atrial flutter; atrial fibrillation; ventricular tachycardia; and ventricular fibrillation. Arrhythmias can be induced in laboratory animals that are suitable experimental models for man to study physiological mechanisms of the disorder or to screen new antiarrhythmic agents.
Clinical treatment of arrhythmias includes administration of a variety of drugs, although quinidine, procainamide, and diphenylhydantoin are current mainstays.
Quinidine is the d-isomer of quinine: ##STR2## while procainamide is p-amino-N-(2-diethylaminoethyl)benzamide: ##STR3## Quinidine and procainamide require extreme care in administration because they are relatively toxic. Because of limitations in those antiarrhythmic drugs, there have been efforts to discover safer substitutes. The discovery of the antiarrhythmic activity of diphenylhydantoin opened new approaches in the design of new compounds exhibiting such activity.
Diphenylhydantoin (5,5-diphenyl-2,4-imidazolidinedione; "DHP"), ##STR4## initially was utilized in the treatment of epilepsy but later was discovered to have important antiarrhythmic applications. The pharmacodynamics of DPH differ from those of quinidine and of procainamide. DPH specifically antagonizes ventricular arrhythmias induced by digitalis, depresses ventricular automaticity, enhances atrio-ventricular nodal conduction, and reduces the effective refractory period. DPH, however, is not without untoward side effects: dizziness, nausea, emesis, nystigmus, and ataxia. DPH is also toxic and may produce atrio-ventricular blockage, bradycardia, or even cardiac arrest accompanying its administration.
For a review of the current status of the field and of DPH as an antiarrhythmic agent, see: G. K. Moe and J. A. Albildskow, "Antiarrhythmic Drugs," in: The Pharmacological Basis of Therapeutics, 5th Edition, L. S. Goodman and A. Gilman, Editors, MacMillan Company, New York, Chapter 32 (1976); and L. S. Dreifus and Y. Watanabe, Amer. Heart J., 80: 709-713 (1970).
2. Description of the Prior Art
Six references report various syntheses of 5-(indol-3-yl)hydantoin, ##STR5## and describe the compound as useful in the preparation of tryptophan or other .alpha.-amino acids; none, however, discloses pharmacological utility of the compound. Those references include: Coker et al., J. Org. Chem., 27: 850 and 3209 (1962); published Japanese patent application No. 19,803/64 (1964); British Pat. Nos. 903,953 and 982,727 (1965); U.S. Pat. No. 3,419,551 (1968); and French Pat. No. 2,079,849 (1971).
Marchant and Harvey (J. Chem. Soc., 1808 [1951])provide details of the synthesis of 5- and 7-methoxytryptophan using 5-methoxyindol-3-yl and 5-[7-methoxyindol-3-yl]hydantoin intermediates respectively. The 5- and 7-methoxytryptophan derivatives are used in studies on tryptophan metabolism.
Finkbinder (J. Org. Chem., 30: 3414 [1965]) teaches use of 3-phenyl-5[(indol-3-yl)methyl]hydantoin in the preparation of trytophan and its analogues.
Published Japanese patent application No. 105716/72 (1974) reveals 5[(indol-3-yl)methyl]-5-methyl hydantoins having the structural formula, ##STR6## in which R is a hydrogen atom or a benzyloxy group. The patent discusses the utility of compounds V in terms of .alpha.-methyltryptophan precursors.
Sagetullin and Koronelli (Vestn. Mosk. Univ., Ser. II, Khim., 19: 68 [1964]) use 5-[(indol-3-yl)methylidene]hydantoin as an intermediate in the synthesis of DL-abrine and 5-methoxyabrine.
U.S. Pat. No. 3,300,510 (1967) teaches that compounds characterized by the structure, ##STR7## in which n is 1, 2, or 3, are mydriatic stimulants, analgesics, and antidepressants.
German Federal Republic Pat. No. 1,944,419 (1971) discloses that compounds having the formula, ##STR8## wherein R is an alkyl group containing 1-4 carbon atoms, or a benzyl group, have antiinflammatory properties.
From the preceding summary of the prior art, it is clear that the disclosed indolylhydantoins fall into two separate categories: (1) intermediates for the preparation of tryptophan and its analogues, which intermediates have no reported pharmacological activity; and (2) pharmacologically active agents of various utility. The latter category includes mydriatic stimulating, analgesic, antidepressant and antiinflammatory utilities but excludes antiarrhythmic utility. The prior art therefore provides no structure-activity relationships suggesting that indolylhydantoins may have antiarrhythmic properties.